Ctla4 And Ptpn22 Associations
Genotypes for SNPs in the PTPN22 region on human chromosome 1p13.2 and in the CTLA4 region on chromosome 2q33.3 were available in a subset of 2,003 NHWs. Of the PTPN22 region SNPs, only the rs2476601 variant in the coding region of PTPN22 , known to be associated with type 1 diabetes risk, is significantly associated with ATP4A autoantibodies . The association of rs2476601 with TPO autoantibodies is relatively weak . There is no evidence of association of PTPN22 rs2476601 with GAD65 autoantibodies , 21-OH autoantibodies , TG autoantibodies , or IA-2 autoantibodies .
Autoantibody-specific ORs for the CTLA4 CT60 variant identified as negatively associated with ATP4A autoantibodies and the PTPN22 R620W variant identified as positively associated with ATP4A autoantibodies in NHW subjects.
Genetics Of Type 1 Diabetes Comes Of Age
Maria J. Redondo, Patrick Concannon Genetics of Type 1 Diabetes Comes of Age. Diabetes Care 1 January 2020 43 : 1618.
Younger age at diagnosis often reflects a greater influence of genetic factors in disease. Type 1 diabetes, which develops most frequently in childhood but can also present in adult life, is a prime candidate to explore the relationships among risk loci, age at diagnosis, and genetic contribution to disease. Type 1 diabetes genetic risk scores are inversely correlated with age at diagnosis. Studies have suggested age-related heterogeneity in the association of established risk alleles with type 1 diabetes, although no consistent pattern has developed. Further investigations into the genetic factors that influence age of clinical onset may refine our understanding of type 1 diabetes pathogenesis and provide opportunities for individualized preventive therapies.
Pathway Analysis And Functional Gene Annotations
Biological pathway enrichments for the differentially expressed genes were identified using the R software package with a significance threshold of p value< 0.05 threshold. R software package was used for the tissue-specific gene expression analysis. PubTator Central was used for manual literature curation to examine the molecular and phenotypic implications of specific examples of differentially expressed genes.
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What Is The Major Susceptibility Gene For Type 1 Diabetes
BACKGROUND Type 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic cells. The major susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed.
Can we determine extreme genetic risk for Type 1 diabetes?
Determining extreme genetic risk is a prerequisite for the implementation of primary prevention trials, which are now underway for relatives of individuals with type 1 diabetes. Type 1 diabetes , 2 a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic cells.
How should we study the genetics of Type 1 diabetes mellitus ?
Two major approaches have been used to study the genetics of T1D, namely candidate gene association studies and genome-wide linkage analysis studies ).
Genetics And The Stages Of Type 1 Diabetes
The onset of T1D symptoms is the clinical manifestation of the disease process that results from the interaction of predisposing genetic factors with environmental exposures, which eventually leads to a T-cell mediated, B-cell facilitated, autoimmune attack on beta-cells. The presence of islet cell autoantibodies is presently the earliest and more robust biomarker of islet autoimmunity. Autoantibody responses to at least two islet antigens define the first stage of T1D at this point remissions are rare. Stage 2 T1D is defined as the presence of two or more islet autoantibodies and dysglycemia, that is, glucose metabolism abnormalities that do yet not meet diabetes criteria. Stage 3 develops when the established glycemic thresholds for diabetes diagnosed are exceeded. Although remissions after Stage 1 are rare, the risk and rate of progression vary based upon genetics, age at seroconversion, autoantibody titers and body mass index .
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Type 2 Diabetes And Genetics Average Risks
- If either mother of father has diabetes increases risk of diabetes by 15%
- If both mother and father have diabetes increases risk by 75%
- If non-identical twin has diabetes increases risk by 10%
- If identical twin has diabetes increases risk by 90%
Some other forms of diabetes may be directly inherited, including maturity onset diabetes in the young and diabetes due to mitochondrial DNA mutation.
However, neither type 1 or type 2 diabetes may be entirely genetically determined.
Experts believe that environmental factors act as either initators or accelerators.
Several genes are known as susceptibility genes, meaning that if an individual is carrying this gene they face greater risk of developing diabetes.
Similarly, other genes provide greater immune tolerance for non-diabetics.
Papers Of Particular Interest Published Recently Have Been Highlighted As: Of Importance Of Major Importance
Steyn NP, Lambert EV, Tabana H. Conference on multidisciplinary approaches to nutritional problems. Symposium on diabetes and health. Nutrition interventions for the prevention of type 2 diabetes. Proc Nutr Soc. 2009 68:5570. .
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007 447:66178. .
Noble JA, Valdes AM, Cook M, Klitz W, Thomson G, Erlich HA. The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Hum Genet. 1996 59:113448.
Mueller PW, Rogus JJ, Cleary PA, Zhao Y, Smiles AM, Steffes MW, et al. Genetics of Kidneys in Diabetes study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes. J Am Soc Nephrol. 2006 17:178290. .
Cooper JD, Walker NM, Healy BC, Smyth DJ, Downes K, Todd JA. Analysis of 55 autoimmune disease and type II diabetes loci: further confirmation of chromosomes 4q27, 12q13.2 and 12q24.13 as type I diabetes loci, and support for a new locus, 12q13.3-q14.1. Genes Immun. 2009 10:S95120. .
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What Are My Odds Of Getting Type 1 Diabetes If My Sibling Has It
If your brother or sister has type 1 diabetes, your risk is about 1 in 20 or a 5% chance of developing it. Having an identical twin with type 1 diabetes also increases your odds as you share the same genes. If your identical twin has type 1 diabetes, then you may have a 50% chance of developing type 1 diabetes yourself.
Evidence For The Contribution Of Genetics To Type 1 Diabetes
Two major approaches have been used to study the genetics of T1D, namely candidate gene association studies and genome-wide linkage analysis studies ). Both approaches, although not devoid of challenges ), have resulted in an abundance of knowledge about genes and loci that confer risk and protection for T1D.
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Hla Class I And Class Iii Alleles
Recently, evidence has been found for susceptibility loci within or linked to the MHC independent of HLA-DR/DQ, such as HLA class I alleles . In the Diabetes Autoimmunity Study in the Young cohort, siblings of children with T1D who have HLA DR3/DR4-DQB1*0302 and are identical by descent for both HLA haplotypes with their diabetic proband sibling were observed to have a 65% risk for developing islet autoantibodies by age 7 years and a 50% risk of developing diabetes by age 10 years . These findings suggest that additional MHC-linked genes determine T1D risk.
HLA-A is associated with T1D independent of DR/DQ . Allele A24 has been associated with younger age of onset allele A30 is higher risk whereas allele A1 is lower risk than other DR3 haplotypes. HLA-B and HLA-C alleles have also been associated with T1D independent of DR/DQ . After adjustment for linkage disequilibrium with DR/DQ, the alleles HLA-B18, B39, B44, C3, C8, and C16 remained associated with T1D . In a study by Nejentsev et al., both HLA-A and HLA-B survived correction for HLA-DR and DQ, and in particular, HLA-B39 was observed to confer high risk for T1D and was associated with lower age of onset .
What Leads To Diabetes
Type 1 and type 2 diabetes have different causes, but there are two factors that are important in both. You inherit a predisposition to the disease, then something in your environment triggers it.
Thats right: genes alone are not enough. One proof of this is identical twins. Identical twins have identical genes. Yet when one twin has type 1 diabetes, the other gets the disease, at most, only half the time. When one twin has type 2 diabetes, the other’s risk is three in four at most.
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Genetic Correlation And Snp Heritability Analyses
We employed the recently developed HDL method to estimate the genetic correlation between T1D and T2D, together with obesity and body mass index using population-level data from the UKBB. The genome-wide genotype data available in the UKBB is obtained from a large prospective cohort study of~500,000 individuals across the United Kingdom, providing a rich resource for genetic analyses. Genetic correlation and SNP heritability analyses for the phenotypes in this report were conducted as described on . Briefly, the UKBB summary statistics of genome-wide associations for T1D, T2D, BMI and obesity were obtained from the Neale lab . The association tests on curated phenotypes were performed on 361,194 unrelated individuals of British ancestry as described on . Computed linkage disequilibrium matrices and imputed reference panels of HapMap3 SNPs were downloaded from . The imputed panel of SNPs was used as it provides a more accurate estimate of genetic correlations .
Causes Of Type 1 Diabetes
If you have just been diagnosed with type 1 diabetes you are probably wondering, ‘why me?’
It is important to know it is not your fault that you have type 1 diabetes it is not caused by poor diet or an unhealthy lifestyle. In fact, it isnt caused by anything that you did or didnt do, and there was nothing you could have done to prevent it.
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How 2 Type 1
Do you live with type 1 diabetes? Do you care for someone who does? Whether you’ve been recently diagnosed or living with the disease for years, How 2 Type 1 is for you. This video, developed in partnership with the Diabetes Leadership Foundation, aims to provide support, knowledge, expert advice, and actionable steps to help you and others in the type 1 diabetes community thrive!
Whats The Difference Between Type 1 And Type 2 Diabetes
While both type 1 and type 2 diabetes occur when the pancreas cant make enough insulin for what the body needs, this lack of insulin happens for very different reasons.
Insulin is a hormone that acts on many different organs in the body, helping them to use nutrients like glucose, fats, and proteins, Laura C. Alonso, M.D., distinguished professor of medicine, chief of the Division of Endocrinology, Diabetes, and Metabolism, and director of the Weill Center for Metabolic Health, tells SELF.
Type 1, which usually starts in childhood and is seen more often in those of European ancestry, is an autoimmune disease. The bodys immune system kills the insulin-producing beta cells in the pancreas, Siripoom McKay, M.D., an assistant professor of pediatrics in diabetes and endocrinology at Baylor College of Medicine and medical director of inpatient diabetes at Texas Childrens Hospital, tells SELF. Losing the majority of beta cells requires insulin therapy to lower glucose levels.
Simply put, people with type 1 diabetes have to take insulin every day to stay alive. .
Type 2 diabetes, on the other hand, results from changes in the body that make it difficult for your pancreas to produce enough insulin, along with your body not using insulin efficiently . As the disease progresses, people with type 2 diabetes may also have to take insulin, but there are a number of other medications and lifestyle changes that can help, too, according to the ADA.
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Hla Associations With T1d
Sorting out HLA associations is complicated not only by the extremely large numbers of reported alleles at the HLA genetic loci but also by differences in allele frequencies and haplotypic combinations among populations, incomplete penetrance of the HLA susceptibility loci, and epistatic interactions of HLA with other susceptibility factors. Studies of HLA association with T1D have been ongoing for nearly 40 years. By far, the majority of studies of HLA association with T1D have used Caucasian subjects. Although great advances have been made, more is still to be learned, especially in non-Caucasian populations.
What Is Type 1 Diabetes
Type 1 diabetes is an autoimmune disease which interferes with one of biology’s most fundamental processes: making sure sugar is available to fuel our bodies.
In a nutshell, a rogue immune system mistakenly destroys the pancreatic beta cells which produce insulin. We need insulin to move sugar from food out of our blood and into cells where it is stored for energy. Without insulin, sugar levels rise to stratospheric levels and can lead to coma and even death.
Type 1 diabetes is a lifelong disease which requires lifelong insulin replacement therapy to manage it.
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Genes Ethnicity And Geography May All Play A Role
There are several risk factors that may make it more likely that youll develop type 1 diabetesif you have the genetic marker that makes you susceptible to diabetes. That genetic marker is located on chromosome 6, and its an HLA complex. Several HLA complexes have been connected to type 1 diabetes, and if you have one or more of those, you may develop type 1. actually develop type 1.)
Other risk factors for type 1 diabetes include:
Viral infections: Researchers have found that certain viruses may trigger the development of type 1 diabetes by causing the immune system to turn against the bodyinstead of helping it fight infection and sickness. Viruses that are believed to trigger type 1 include: German measles, coxsackie, and mumps.
- American Diabetes Association. Standards of Medical Care in Diabetes2009. Diabetes Care. 2009 32:S13-61.
Regulatory Snpgene Interactions And Eqtls Analyses
We identified genes whose transcript levels depend on the identity of the T1D-associated SNP using the CoDeS3D algorithm . Initially, the modular python scripts that comprise CoDeS3D use 1 kb resolution Hi-C contacts from non-synchronized immortalized human cell lines to identify spatial co-localization of two DNA regions, one of which is marked by a SNP. These spatially associating genomic regions are not limited to adjacent regions within the linear DNA sequence .
Next, data from the Genotype-Tissue Expression database is incorporated to address whether spatially associated T1D-SNPs are associated with changes in the transcript levels of the spatially associated genes. The gene list and DNA locations are based on the hg19/GRCh37 human genome reference. The CoDeS3D analysis identifies: SNP-gene pairs that spatially co-localize within the nucleus SNP-gene pairs that are expression QTLs and the tissues in which the eQTL is significant, using the BenjaminiHochberg correction for multiple testing . Although the multiple testing burden of eQTL mapping can bias or misinterpret results, our FDR threshold has been demonstrated to identify biologically significant associations consistently . Cis-expression QTL SNPs were defined as occurring within loci < 1 Mb. By contrast, trans-expression QTL SNPs were defined as occurring between loci > 1 Mb apart, or on different chromosomes.
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Identification Of T1d Associated Snps
Single nucleotide polymorphisms associated with T1D were selected from the manually curated Catalog of Published Genome-Wide Association Studies 1 . These SNPs represent the 60 susceptibility regions that are typically associated with T1D. Equally sized sets of control SNPs were randomly selected from the SNP database using a Python script.
Genetics Coming Of Age In Type 1 Diabetes
Karen Cerolsaletti, Wei Hao, Carla J. Greenbaum Genetics Coming of Age in Type 1 Diabetes. Diabetes Care 1 February 2019 42 : 189191.
GWAS have revealed several important aspects of T1D disease etiology. First, the majority of genes associated with T1D function in the immune system, underscoring the immune basis of disease initiation and progression . Second, GWAS have identified pathways that are important in disease pathogenesis, such as variants in the interleukin-2 signaling pathway that are associated with disease . Third, T1D GWAS studies have identified a shared genetic architecture with other autoimmune diseases , indicating common pathogenic mechanisms and the possibility of repurposing therapies for T1D that are in use for other autoimmune diseases. Additionally, genotype-phenotype studies have provided important windows into disease pathogenesis by revealing alterations in B-cell and T-cell development, tolerance checkpoints, regulatory T-cell fitness, and cytokine signaling .
Several recent articles in Diabetes Care describe the use of genetics to improve diagnosis and prediction of disease progression in T1D as well as progression to insulin use in type 2 diabetes .
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What Is Genetic Susceptibility To Diabetes
The insulin receptor gene on chromosome 19p13 and at least five glucose transporter genes contribute to Type 2 diabetes susceptibility, and further associations may emerge from study of the glycogen synthase gene, the glucokinase gene, the MODY genes, and the leptin gene.
What percent of type 1 diabetes is genetic?
Family History of Type 1 Diabetes Although more than 85% of patients with T1D lack a positive family history for the disease, there is high familial clustering with a mean prevalence of 6% in siblings compared to 0.4% in the US white population.
What triggers type 1 diabetes?
What causes type 1 diabetes? Type 1 diabetes occurs when your immune system, the bodys system for fighting infection, attacks and destroys the insulin-producing beta cells of the pancreas. Scientists think type 1 diabetes is caused by genes and environmental factors, such as viruses, that might trigger the disease.